ClinVar Miner

Submissions for variant NM_003119.4(SPG7):c.1053dup (p.Gly352fs) (rs760818649)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000627428 SCV000859029 pathogenic not provided 2018-01-02 criteria provided, single submitter clinical testing
GeneDx RCV000627428 SCV000748426 pathogenic not provided 2017-10-12 criteria provided, single submitter clinical testing The c.1053dupC variant in the SPG7 gene has been reported previously, in the homozygous state and in conjuction with another pathogenic SPG7 variant, in multiple individuals with SPG7-related disorders (Tzoulis et al., 2008; Pfeffer et al., 2015; Keogh et al., 2015). The c.1053dupC variant causes a frameshift starting with codon Glycine 352, changes this amino acid to a Arginine residue, and creates a premature Stop codon at position 44 of the new reading frame, denoted p.Gly352ArgfsX44. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.1053dupC variant is observed in 9/23,940 (0.04%) alleles from individuals of African background, in large population cohorts (Lek et al., 2016).
Invitae RCV000461092 SCV000552953 pathogenic Spastic paraplegia 7 2018-06-11 criteria provided, single submitter clinical testing This sequence change inserts 1 nucleotide in exon 8 of the SPG7 mRNA (c.1053dupC), causing a frameshift at codon 352. This creates a premature translational stop signal (p.Gly352Argfs*44) and is expected to result in an absent or disrupted protein product. Truncating variants in SPG7 are known to be pathogenic (PMID: 21623769). This variant has been reported in either the homozygous or compound heterozygous state in individuals affected with hereditary spastic paraplegia (HSP) (PMID: 25681447, 23733235, 24727571, 23065789). In one family, this variant has been reported to segregate with HSP (PMID: 18563470). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000824802 SCV000731818 pathogenic Hereditary spastic paraplegia 2017-08-02 criteria provided, single submitter clinical testing The p.Gly352ArgfsX44 (NM_003119.2 c.1053dup) (also referred to as c.1053_1054ins C or c.1047insC in the literature) variant in SPG7 has been reported in 7 compou nd heterozygous and 2 homozygous individuals with clinical diagnosis of heredita ry spastic paraplegia or ataxia, and segregated in two affected homozygous sibli ngs in one family (Tzoulis 2008, Klebe 2012, van Gassen 2012, Yoon 2013, Pfeffer 2015, Rydning 2016). This variant has also been reported in ClinVar (Variation ID#411675) as pathogenic by one laboratory. It has been identified in 23/125,780 European chromosomes by the Genome Aggregation Database (http://gnomad.broadins; rs760818649). This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 352 and leads to a premature termination codon 44 amino acids downstream. This alteration is the n predicted to lead to a truncated or absent protein. Biallelic loss of function of the SPG7 gene has been associated with hereditary spastic paraplegia. In sum mary, the p.Gly352ArgfsX44 variant meets criteria to be classified as pathogenic for hereditary spastic paraplegia in an autosomal recessive manner based on its biallelic occurrence in individuals with this disease and its predicted null ef fect.

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